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Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial

BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n84 (Published 20 January 2021) Cite this as: BMJ 2021;372:n84

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Covid-19 controversies: the tocilizumab chapter

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Tocilizumab for COVID-19: Difficulties in Interpreting the Results of RCTs vs. Observational Studies

Dear Editor

The anti-inflammatory properties of tocilizumab may have benefit for subjects with COVID-19. However, identifying appropriate therapies for the disease proves to be extremely challenging. The complex natural history of COVID-19, which includes an early "viral" phase overlapping a later "inflammatory" phase, may result in potential therapies being effective only during limited timeframes, which are currently difficult to identify. Additionally, critically ill patients suffer systemic and multi-organ complications, and are also prone to secondary infections.
Bacterial co-infection is common in subjects with severe COVID-19, and associated with worse outcome. [1] One of the reasons for the success of tocilizumab in retrospective and observational studies, such as the large study by Gupta et al. [2] may be a selection bias for the control group. It is highly probable that immunosuppressive medications such as tocilizumab will only be administered to subjects without evidence of bacterial co-infection. Thus, in retrospective studies the control group will include more subjects with such secondary infections, which have inherently worse outcomes. If this is the case, the perceived benefit of tocilizumab may simply be the confounding effect of unmatched study groups. This may explain some of the critical differences in the results between prospective, randomized controlled trials, and retrospective, observational trials.
In our hospital, we consider tocilizumab for critically ill subjects with COVID-19, after excluding concomitant bacterial infection using molecular diagnostic tests from lower respiratory tract specimens. We believe that such tests offer a high negative predictive value for co-infection with a rapid turnover time, although at the cost of "false positive" results. [3]
Understanding and interpreting the results of COVID-19 trials has other potential difficulties. For example, the time since the beginning of symptoms to hospital admission can affect outcome as was demonstrated by Alaa et al [4]. Therefore, different policies of referral to hospital is another variable that is not commonly taken into account.
Even though Veiga et al. report no benefit, and possible harm, from tocilizumab in subjects with COVID-19 [5], as beautifully summarized in the Editorial [6], the role of tocilizumab in COVID-19 is still undefined and we will have to await the results of further studies.

References
1. Zhou F, Yu T, Du R, et al. Clinical Course and Risk Factors for Mortality of Adult Inpatients with COVID-19 in Wuhan, China: A Retrospective Cohort Study. Lancet 2020; 395:1054-62.
2. Gupta S, Wang W, Hayek SS, et al. Association between Early Treatment with Tocilizumab and Mortality among Critically Ill Patietns with COVID-19. JAMA Intern Med 2021; 181:41-51.
3. Kolenda C, Ranc AG, Boisset S, et al. Assessment of Respiratory Bacterial Coinfections Among Severe Acute Respiratory Syndrome Coronavirus 2-Positive Patients Hospitalized in Intensive Care Units Using Conventional Culture and BioFire, FilmArray Pneumonia Panel Plus Assay. Open Forum Infec Dis 2020; 7(11):ofaa484. doi: 10.1093/ofid/ofaa484. eCollection 2020 Nov.
4. Alaa A, Qian Z, Rashbass J et al. Retrospective Cohort Study of Admission Timing and Mortality Following COVID-19 Infection in England. BMJ Open 2020; 10(11):e042712.
5. Veiga VC, Prats JAGG, Farias DLC, et al. Effect of Tocilizumab on Clinical Outcomes at 15 days in Patients with Severe or Critical Coronavirus Disease 2019: Randomised Controlled Trial. BMJ 2021; 372:n84. doi: 10.1136/bmj.n84.
6. McCreary EK and Meyer NJ. COVID-19 Controversies: The Tocilizumab Chapter. BMJ 2021; 372:n244. doi: 10.1136/bmj.n244.

Competing interests: No competing interests

07 February 2021
Ori Wand
Senior Physician
Daniel A King
Pulmonary Department and Respiratory Intensive Care Unit, Meir Medical Center, Kfar-Sava, Israel
Meir Medical Center, Tchrenichovsky 59, Kfar-Sava, 442801, Israel